Rapid gains in genetics and genomics pose both great opportunities and challenges for the contemporary physician. The developmental goals of this K24 are intended to train and mentor patient-oriented physician scientists to conduct innovative research that will transform molecular genetics into molecular medicine. The applicant is a mid-career clinician-scientist whose investigational program focuses on applications of genomic science to the management of hereditary melanoma patients. The candidate is widely recognized for his contributions in the genetics of melanoma predisposition and progression. He founded and directs a vibrant Melanoma Genetics Program at the Massachusetts General Hospital (MGH), established a rich Hereditary Melanoma Registry at Harvard with over 250 melanoma families from throughout the world and leads both the Skin Cancer Genetics Laboratory in the Wellman Center for Photomedicine and the MGH Melanoma and Pigmented Lesion Center- a clinical unit dedicated to the care of melanoma patients; this multidisciplinary infrastructure provides unique opportunities to bring basic discoveries to the bedside. The applicant has mentored many medical students, specialty and subspecialty trainees and postdoctoral fellows in the proper conduct of patient-oriented molecular research. The mentorship plan includes a set of core training objectives: (1) to develop facility in skills required for academic success including the ability to execute the fundamentals of sound science, to write grants and manuscripts with coherence and cogency and to deliver a concise and convincing presentation, (2) to critically evaluate science for design and interpretation, (3) to effectively frame the scientific method from techniques to experiments to projects and finally to programs and (4) to mature within the context of a scientific community. These will be achieved through the execution of 4 broad scientific Aims: (1) create a robust model (termed MelaPRO) to estimate CDKN2A/CDK4 mutation carrier probability, (2) identify coding variants in RB-pathway genes in high-risk families lacking CDKN2A/CDK4 alterations (3) develop a flexible, accurate, high-throughput platform to assess CDKN2A/CDK4/MC1R genotypes and (4) devise novel functional assays for patient-derived variants in the melanocortin-1-receptor (MC1R) gene. Through the proposed K24 mid-career development award, the applicant will be able to develop several tangible products for the melanoma patient, to expand his own knowledge of important emerging area of variomics and, most importantly, to find the necessary time to mentor trainees and junior faculty and sustain a productive research laboratory. PUBLIC HEALTH RELEVANCE: The scientific momentum ignited by the Human Genome Project has created unprecedented opportunities and challenges for medicine. In cutaneous melanoma, as in many other fields, an enlarging gulf divides the molecular scientist at the benchside and the clinician/researcher at the bedside. This K24 application is aimed at mentoring and training the next generation of patient-oriented physician-scientists to bridge this gap and to bring genetic discoveries to individuals and families affected by melanoma.